Methods and compositions for picornavirus anti-viral agents

Abstract

Disclosed are methods and compositions for treating or preventing a disease, a disorder, or symptom associated with picornaviruses in a subject including a therapeutically effective amount of a compound of Formula I, Formula II, or a pharmaceutically acceptable salt thereof, wherein X, Y, L, A, B, A1, A2, A3, R1, R2, R3, R4, R7, R8, R9, and R10 are as described herein.

What is claimed is: 
     
         1 . A method of treating or preventing a disease or disorder, or a symptom associated with a picornavirus infection in a subject, the method comprising:
 providing and administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a composition comprising the same to the subject, wherein Formula I has the chemical structure:   
       
         
           
           
               
               
           
         
         wherein in Formula I, 
         X is CR 5  or N; 
         Y is CR 5 R 6 , NR 5 , O, or S; 
         L is a linker comprising O, NR 5 , CONR 5 , COO, COS, or S; 
         A 1  and A 2  are each independently an aryl (such as a monocyclic aryl or bicyclic aryl), a heteroaryl (such as a monoheteroaryl or bicyclic heteroaryl), an aryloxy (such as phenoxy), a thioaryl (such as thiophenyl), an alkyl (such as C 1 -C 6  alkyl), an alkylene (such as a C 2-6  alkylene), an alkenyl (such as a C 2-6  alkenyl, ethenyl, or propenyl), an alkynyl (such as a C 2-6  alkynyl or acetylenyl), a haloalkyl (such as C 1 -C 6  haloalkyl), an alkoxy (such as C 1 -C 6  alkoxy), a cycloalkyl (such as a C 3 -C 8  cycloalkyl group), a heterocycloalkyl (such as a 5-8 membered heterocycloalkyl), an alkylaryl (such as a C 1-3  alkyl-C 8-11  aryl, C 1-3  alkyl-C 6  aryl, C 1-3  alkyl-C 8  aryl, or C 1-3  alkyl-C 11  aryl), an alkylheteroaryl (such as a C 1-3  alkyl-5-11 membered heteroaryl or C 1-3  alkyl-5-8 membered heteroaryl), or a (cycloalkyl)alkyl (such as C 1-3  alkyl-C 3-8  cycloalkyl),
 wherein A 1  and A 2  are each optionally substituted with one or more (such as 1, 2, 3, 4, or more) substituents independently selected from halogen, hydroxyl, cyano, nitro, amino, alkyl (such as C 1 -C 6 alkyl), alkoxy (such as C 1 -C 4  alkoxy or methoxy), cycloalkyl (such as C 3 -C 8  Cycloalkyl), haloalkyl (such as C 1 -C 2 haloalkyl), haloalkoxy (such as C 1 -C 2 haloalkoxy), aryl (such as a C 6  or C 8  aryl), heteroaryl (such as a 5-8 membered heteroaryl), heterocycloalkyl (such as a 3-8 or 5-8 membered heterocycloalkyl), an aryloxy (such as C 6  or C 8  aryloxy or phenoxy), a thioaryl (such as C 6  or C 8  thioaryl thiophenyl), —CHO, —COOH, —CONR 5 R 6 , —COR 5 , —NO 2 , —O—CO—R 6 , —NR 5 —CO—R 6 , and hydrocarbyl having a hydrocarbon chain of 1 to 6 carbon atoms in which the carbon atoms are joined by single, double or triple bonds, and any one carbon atom or any two nonadjacent carbon atoms can be replaced by O, NH, N(C 1 -C 4  alkyl), or S, wherein the hydrocarbyl group is optionally substituted with one or more substituents independently chosen from hydroxyl, oxo, halogen, and amino; and 
 
         R 1 , R 2 , R 3 , R 4 , R 5 , and R 6  are each independently hydrogen, halogen, hydroxyl, cyano, nitro, amino, —CHO, —CONH 2 , —CO-aryl (such as benzoyl), —CO-alkyl (such as acetyl), alkyl (such as C 1 -C 6  alkyl), alkoxy (such as C 1 -C 4 alkoxy), cycloalkyl (such as C 3 -C 8  cycloalkyl), haloalkyl (such as C 1 -C 2 haloalkyl), haloalkoxy (such as C 1 -C 2 haloalkoxy), aryl (such as a C 6-11  aryl, a C 6 , C 8  or C 11  aryl, phenyl, naphthyl, or tolyl), heteroaryl (such as 5-8 membered heteroaryl, furyl, or benzofuryl), heterocycloalkyl (such as a 3-8 membered heterocycloalkyl), an aryloxy (such as phenoxy), alkylaryl (such as —CH 2 —CH 2 -Ph), or a thioaryl (such as thiophenyl); 
         wherein two adjacent R groups, R 1  and R 2 , R 2  and R 3 , or R 3  and R 4  are optionally combined together with the carbon atoms they are attached to form a 6- or 8-membered aromatic ring or a 5-8 membered heteroaromatic ring, 
         wherein A 2  is optionally substituted by one substituent having the structure —CONR 5a R 6a (such as —CONHR 6a ), wherein R 5a  is hydrogen or a C 1-3  alkyl, and R 6a  is a bicyclic heteroaryl (such as a 9-11 or 10 membered bicyclic heteroaryl) or a C 6  or C 8  aryl substituted with a bicyclic heteroaryl (such as a 9-11 or 10 membered bicyclic heteroaryl), and 
         wherein the method is effective in treating, preventing, or ameliorating the disease or disorder associated with a picornavirus infection, or at least one symptom of the disease or disorder associated with a picornavirus infection. 
       
     
     
         2 . The method of  claim 1 , wherein:
 A 1  is an monocyclic aryl (such as a C 6  or C 8  aryl), a monocyclic heteroaryl (such as a 5-8 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from N, O, and S), a mono cycloalkyl (such as a C 3-8  cycloalkyl), or a mono heterocycloalkyl (such as a 5-8 membered heterocycloalkyl having 1, 2, or 3 heteroatoms independently selected from N, O, and S);   A 2  is an alkyl (such as C 1-6  alkyl) optionally having a heteroatom (such as NH, O, or S) replacing one of the carbon atoms, alkylene (such as such as a C 2-6  alkylene), alkenyl (such as a C 2-6  alkenyl, ethenyl, or propenyl), alkynyl (such as a C 2-6  alkynyl or acetylenyl), a haloalkyl (such as C 1-6 haloalkyl), cycloalkyl (such as a C 3-8  cycloalkyl group), monocyclic aryl (such as phenyl), —CH 2 -thioaryl (such as a C 6  or C 8  thioaryl), bicyclic aryl (such as a monocyclic aryl or bicyclic aryl), monocyclic heteroaryl (such as a 5-8 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from N, O, and S), aryloxy (such as a C 6  or C 8  aryloxy or phenoxy), thioaryl (such as thiophenyl), a bicyclic heteroaryl (such as a 9-11 membered heteroaryl having 1, 2, 3, 4, or 5 heteroatoms independently selected from N, O, and S), alkoxy (such as C 1-6  alkoxy), alkylaryl (such as a C 1-3  alkyl-C 6-11  aryl, C 1-3  alkyl-C 6  aryl, C 1-3  alkyl-C 8  aryl or C 1-3  alkyl-C 11  aryl), alkylheteroaryl (such as a C 1-3  alkyl-5-8 membered heteroaryl), (cycloalkyl)alkyl (such as C 1-3  alkyl-C 3-8  cycloalkyl), (heterocycloalkyl)alkyl (such as C 1-3  alkyl-3-8 membered cycloalkyl);   R 1 , R 2 , R 3 , and R 4  are each independently hydrogen, halogen (such as Cl, F, I, or Br), C 1-6  alkyl (such as C 1-3  alkyl or methyl), hydroxyl, cyano, nitro, amino, —CHO, —CONH 2 , —CO-aryl (such as benzoyl), —CO—C 1-6  alkyl (such as acetyl), C 1-4  alkoxy), C 3-8  cycloalkyl), haloalkyl (such as C 1 -C 2 haloalkyl), haloalkoxy (such as C 1 -C 2 haloalkoxy), aryl (such as a C 6 , C 8  of C 11  aryl, phenyl, naphthyl, or tolyl), 5-8 membered heteroaryl (such as a 5- or 6-membered heteroaryl), 3-8 membered heterocycloalkyl (such as a 5- or 6-membered heterocycloalkyl), C 6  or C 8  aryloxy (such as phenoxy), C 1-3  alkyl-C 6  or C 8  aryl (such as —CH 2 —CH 2 -phenyl), or a thioaryl (such as thiophenyl); or   a combination thereof,   wherein:
 when A 2  is an alkyl, alkylene, alkenyl or alkynyl, (i) R 2  is an alkyl (such as methyl, ethyl, or propyl), (ii) R 2  and R 3  combined together with the carbon atoms they are attached to form a C 6  aryl, C 8  aryl, or 5-8 membered heteroaryl, or (iii) A 2  is substituted by an aryl (such as a C 6  or C 8  aryl), aryloxy (such as a C 6  or C 8  aryloxy), or a thioaryl (such as a C 6  or C 8  thioaryl), each of which are optionally substituted with one or more (such as 1, 2, 3, 4, or more) substituted independently selected from halogen (such as Cl, Br, I, or F), C 1-3  alkyl (such as methyl); 
 A 2  is optionally substituted by one —CONR 5 R 6a  or one or more (such as 1, 2, 3, 4, or more) substituent independently selected from halogen (such as Br or Cl), oxo, hydroxyl, C 1-3  alkyl, a C 1-3  alkoxy (such as methoxy), —CHO, —COOH, —CONR 5 R 6 , —COR 5 , —NO 2 , —O—CO—R 5 , —NR 5 —CO—R 6 , C 3-8  membered cycloalkyl, a 3-8 membered heterocycloalkyl having 1, 2 or 3 heteroatoms independently selected from N, O and S, C 6  or C 8  aryl, and 5-8 membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from N, O and S; 
 R 6a  is a bicyclic heteroaryl (such as a 9-11 or 10 membered bicyclic heteroaryl) or a C 6  or C 8  aryl substituted with a bicyclic heteroaryl (such as a 9-11 or 10 membered bicyclic heteroaryl); 
 each R 5  is independently H or —CH 3 , wherein each cyclic substituent is optionally substituted with one or more (such as 1, 2, 3, 4, or more) substituted independently selected from halogen (such as Cl, Br, I, or F), C 1-3  alkyl (such as methyl), and —NO 2 ; and 
 each R 6  is independently H or —CH 3 , wherein each cyclic substituent is optionally substituted with one or more (such as 1, 2, 3, 4, or more) substituted independently selected from halogen (such as Cl, Br, I, or F), C 1-3  alkyl (such as methyl), and —NO 2 . 
   
     
     
         3 . The method of  claim 2 , wherein:
 A 1  is a 6-membered aryl or heteroaryl;   L is CONH;   R 1  and R 4  are hydrogen;   R 2  is a hydrogen or a C 1-3  alkyl and R 3  is hydrogen, or R 2  and R 3  are combined together with the carbon atoms they are attached to form a C 6  aryl;   X is N; or   a combination thereof.   
     
     
         4 . The method of  claim 2 , wherein A 1  is a 6-membered aryl or heteroaryl with the chemical structure 
       
         
           
           
               
               
           
         
       
       wherein each Z is independently a CH or N, wherein there 0, 1, 2, 3, or 4 N groups. 
     
     
         5 . The method of  claim 2 , wherein:
 A 1  is a 6-8 membered monocyclic aromatic group comprising 1, 2, or 3 heteroatoms selected from O, S, and N (e.g., C 6  aryl, C 8  aryl, or a 5-8 membered heteroaryl, such as, 5-7 membered heteroaryl or a 6-membered heteroaryl);   A 2  is a C 1-6  alkyl, cycloalkyl (e.g., C 3-8  cycloalkyl), C 6-11  aryl, or 5-8 membered heteroaryl, wherein A 2  is optionally substituted by one or more (such as 1, 2, 3, 4, or more) substituent independently selected from halogen (such as Br or Cl), oxo, hydroxyl, C 1-3  alkyl, a C 1-3  alkoxy (such as methoxy), —CHO, —COOH, —CONR 5 R 6 , —COR 5 , —NO 2 , —O—CO—R 5 , —NR 5 —CO—R 6 , C 3-8  membered cycloalkyl, a 3-8 membered heterocycloalkyl having 1, 2 or 3 heteroatoms independently selected from N, O and S, C 6  or C 8  aryl, and 5-8 membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from N, O and S;   L is CONR 5 , wherein R 5  is a H or C 1-3  alkyl;   R 3  is hydrogen and R 2  is a hydrogen, halogen, or a C 1-3  alkyl, or R 2  and R 3  are combined together with the carbon atoms they are attached to form a 6-membered aryl or heteroaryl;   X is N or CH;   R 1  and R 4  are each H; or   a combination thereof.   
     
     
         6 . The method of  claim 5 , wherein:
 A 1  is a 6-membered aryl or heteroaryl;   L is CONH;   R 1  and R 4  are hydrogen;   R 2  is a hydrogen or a C 1-3  alkyl and R 3  is hydrogen, or R 2  and R 3  are combined together with the carbon atoms they are attached to form a C 6  aryl;   X is N;   a combination thereof.   
     
     
         7 . The method of  claim 6 , wherein A 1  is a 6-membered aryl or heteroaryl with the chemical structure 
       
         
           
           
               
               
           
         
       
       wherein each Z is independently a CH or N, wherein there 0, 1, 2, 3, or 4 N groups. 
     
     
         8 . The method of  claim 1 , wherein the compound is selected from compounds 1-50. 
     
     
         9 . A method of treating or preventing a disease or disorder, or a symptom associated with a picornavirus infection in a subject, the method comprising:
 providing and administering a therapeutically effective amount of a compound of Formula II, or a pharmaceutically acceptable salt thereof, or a composition comprising the same to the subject, wherein Formula II has the chemical structure:   
       
         
           
           
               
               
           
         
         wherein in Formula II, 
         A is CR 11  or N; 
         B is CR 11 R 12 , NR 11 , O, or S; 
         A 3  is an aryl (such as a monocyclic aryl or bicyclic aryl), a heteroaryl (such as a monocyclic heteroaryl or bicyclic heteroaryl), an aryloxy (such as phenoxy), a thioaryl (such as thiophenyl), an alkyl (such as C 1 -C 6  alkyl), an alkylene (such as a C 2-6  alkylene), an alkenyl (such as a C 2-6  alkenyl, ethenyl, or propenyl), an alkynyl (such as a C 2-6  alkynyl or acetylenyl), a haloalkyl (such as C 1 -C 6  haloalkyl), an alkoxy (such as C 1 -C 6  alkoxy), a cycloalkyl (such as a C 3 -C 8  cycloalkyl group), a heterocycloalkyl (such as a 5-8 membered heterocycloalkyl), an alkylaryl (such as a C 1-3  alkyl-C 8-11  aryl, C 1-3  alkyl-C 6  aryl or C 1-3  alkyl-C 8  aryl or C 1-3  alkyl-C 11  aryl), an alkylheteroaryl (such as a C 1-3  alkyl-5-11 membered heteroaryl or C 1-3  alkyl-5-8 membered heteroaryl), or a (cycloalkyl)alkyl (such as C 1-3  alkyl-C 3-8  cycloalkyl),
 wherein A 3  is optionally substituted with one or more (such as 1, 2, 3, or more) substituents independently selected from halogen (such as Br, F, I, or Cl), hydroxyl, cyano, nitro, amino (such as —NH 2 ), alkyl (such as C 1 -C 6  alkyl or methyl), alkoxy (such as C 1 -C 4  alkoxy or methoxy), cycloalkyl (such as C 3 -C 8  cycloalkyl), haloalkyl (such as C 1 -C 2 haloalkyl), haloalkoxy (such as C 1 -C 2 haloalkoxy), aryl (such as a C 6  or C 8  aryl), heteroaryl (such as a 5-8 membered heteroaryl), heterocycloalkyl (such as a 3-8 or 5-8 membered heterocycloalkyl), an aryloxy (such as C 6  or C 8  aryloxy or phenoxy), a thioaryl (such as C 6  or C 8  thioaryl or thiophenyl), —CHO, —COOH, —CONR 11 R 12 , —COR 11 , —NR 11 —CO—R 12 , —NR 11a CO—R 12a  (such as —NH—CO—R 12a ), and hydrocarbyl having a hydrocarbon chain of 1 to 6 carbon atoms in which the carbon atoms are joined by single, double or triple bonds, and any one carbon atom or any two nonadjacent carbon atoms can be replaced by O, NH, N(C 1 -C 4  alkyl), or S, and wherein the hydrocarbyl group is optionally substituted with one or more substituents independently chosen from hydroxyl, oxo, halogen, and amino; 
 
         R 11a  is a hydrogen or a C 1-3  alkyl; 
         R 12a  is a monocyclic heteroaryl (such as a 5-8, 5, 6, or 7 membered heteroaryl), a bicyclic heteroaryl (such as a 9-11 or 10 membered bicyclic heteroaryl), a C 6  or C 8  monocyclic aryl, or a bicyclic aryl (such as a C 9-11  or C 10  bicyclic aryl), wherein the R 14a  is optionally substituted with one or more (such as 1, 2, or 3) substituents independently selected from halogen (such as Cl, Br, I, or F), C 1-3  alkyl (such as methyl), and C 1-3  alkoxy (such as methoxy); 
         R 7 , R 8 , R 9 , R 10 , R 11 , and R 12  are each independently hydrogen, halogen, hydroxyl, cyano, nitro, amino, —CHO, —CONH 2 , —NR 13 —CO—R 14 , —CO-aryl (such as benzoyl), —CO-alkyl (such as acetyl), alkyl (such as C 1 -C 6  alkyl or methyl), alkoxy (such as C 1 -C 4  alkoxy), cycloalkyl (such as C 3 -C 8  cycloalkyl), haloalkyl (such as C 1 -C 2 haloalkyl), haloalkoxy (such as C 1 -C 2 haloalkoxy), aryl (such as a C 6-11  aryl, a C 6 , C 8  or C 11  aryl, phenyl, naphthyl, or tolyl), heteroaryl (such as 5-11, 5, 6 or 10 membered heteroaryl, furyl or benzofuryl), heterocycloalkyl (such as a 3-8 membered heterocycloalkyl), an aryloxy (such as phenoxy), alkylaryl (such as —CH 2 —CH 2 -phenyl), or a thioaryl (such as thiophenyl); 
         R 13  and R 14  are each independently hydrogen, halogen, hydroxyl, cyano, nitro, amino, —CHO, —CONH 2 , —CO-aryl (such as benzoyl), —CO-heteroaryl (such as 5-8, 5 or 6 membered heteroaryl), —CO-alkyl (such as acetyl), alkyl (such as C 1 -C 6  alkyl), alkoxy (such as C 1 -C 4  alkoxy), cycloalkyl (such as C 3 -C 8  cycloalkyl), haloalkyl (such as C 1 -C 2 haloalkyl), haloalkoxy (such as C 1 -C 2 haloalkoxy), aryl (such as phenyl, naphthyl, or tolyl), heteroaryl (such as furyl, or benzofuryl), heterocycloalkyl (such as 5-8, 5, or 6 membered heterocycloalkyl), an aryloxy (such as phenoxy), alkylaryl (such as —CH 2 —CH 2 -phenyl), or a thioaryl (such as thiophenyl), wherein R 14  is optionally substituted with one or more (such as 1, 2, or 3) substituents independently selected from halogen (such as Cl, Br, I, or F), C 1-3  alkyl (such as methyl), and C 1-3  alkoxy (such as methoxy; 
         wherein two adjacent R groups, R 7  and R 8 , R 8  and R 9 , or R 9  and R 10  are optionally combined together with the carbon atoms they are attached to form a 6- or 8-membered aromatic ring or 5-8 membered heteroaromatic ring; 
         wherein the method is effective in treating, preventing, or ameliorating the disease or disorder associated with a picornavirus infection, or at least one symptom of the disease or disorder associated with a picornavirus infection. 
       
     
     
         10 . The method of  claim 9 , wherein
 A 3  is a C 6  aryl or 6-membered heteroaryl;   A 3  is optionally substituted with 1 or 2 substituents independently selected from halogen (such as Br, F, I, or Cl), —NR 11a —CO—R 12a  (such as —NH—CO—R 12a ), hydroxyl, cyano, nitro, amino (such as —NH 2 ), C 1-3  alkyl (such as methyl), C 1-4  alkoxy (such as methoxy), C 3-8  cycloalkyl, C 1-2  haloalkyl, C 1-2 haloalkoxy, C 6  aryl, C 8  aryl, 5-8 membered heteroaryl, 3-8 membered heterocycloalkyl (such as 5-8 membered heterocycloalkyl), —CHO, and —COOH;   R 11a  is a hydrogen or a C 1-3  alkyl;   R 12a  is a 5-8 membered heteroaryl (such as 5, 6, or 7 membered heteroaryl), 9-11 membered bicyclic heteroaryl (such as 10 membered bicyclic heteroaryl), C 6  monocyclic aryl, C 8  monocyclic aryl, or C 9-11  bicyclic aryl (such as C 10  bicyclic aryl), wherein the R 14a  is optionally substituted with 1, 2, or 3 substituents independently selected from halogen (such as Cl, Br, I, or F), or C 1-3  alkyl (such as methyl), and C 1-3  alkoxy (such as methoxy);   R 7 , R 9 , and R 10  are each hydrogen;   A is N;   B is NR 11 ;   R 11  is hydrogen or C 1-6  alkyl (such as C 1-3  alkyl or methyl);   R 13  is a hydrogen or a C 1-3  alkyl;   R 14  is hydrogen, alkyl (such as C 1 -C 6  alkyl), alkoxy (such as C 1 -C 4  alkoxy), cycloalkyl (such as C 3 -C 8  cycloalkyl), haloalkyl (such as C 1 -C 2 haloalkyl), aryl (such as phenyl, naphthyl, or tolyl), heteroaryl (such as furyl, thienyl, or pyrrolyl), and heterocycloalkyl (such as 5-8, 5, or 6 membered heterocycloalkyl); a combination thereof; or   a combination thereof.   
     
     
         11 . The method of  claim 10 , wherein A 3  is a C 6  aryl or 6-membered heteroaryl having the chemical structure 
       
         
           
           
               
               
           
         
       
       wherein:
    is the point of attachment with Formula II; 
 each V is independently a CH or N, wherein there 0, 1, 2, 3, or 4 N groups; and 
 R 15 , R 16 , and R 17  are independently selected from halogen (such as Br, F, I, or Cl), —NR 13a COR 14a  (such as —NHCOR 14a ), hydroxyl, cyano, nitro, amino (such as —NH 2 ), C 1-3  alkyl (such as methyl), C 1-4 alkoxy (such as methoxy), C 3-8  cycloalkyl, C 1-2 haloalkyl, C 1-2 haloalkoxy, C 6  aryl, C 8  aryl, 5-8 membered heteroaryl, 3-8 membered heterocycloalkyl (such as 5-8 membered heterocycloalkyl), —CHO, and —COOH, wherein
 one of R 15 , R 16 , and R 17  is a hydrogen; and 
 one of R 15 , R 16 , and R 17  is a hydrogen or a C 1-6  alkyl (such as C 1-3  alkyl or methyl). 
 
 
     
     
         12 . The method of  claim 9 , wherein:
 A 3  is an aryl (such as C 6  or C 8  aryl), a heteroaryl (such as 5-8 membered heteroaryl), a cycloalkyl (such as a C 3-8  cycloalkyl group), or a heterocycloalkyl (such as a 5-8 membered heterocycloalkyl),   A 3  is optionally substituted with one or more (such as 1 or 2) substituents independently selected from halogen (such as Br, F, I, or Cl), —NR 11a —CO—R 12a  (such as —NH—CO—R 12a ), hydroxyl, cyano, nitro, amino (such as —NH 2 ), C 1-3  alkyl (such as methyl), C 1-4  alkoxy (such as methoxy), C 3-8  cycloalkyl, C 1-2 haloalkyl, C 1-2 haloalkoxy, C 6  or C 8  aryl, 5-8 membered heteroaryl, 3-8 membered heterocycloalkyl (such as 5-8 membered heterocycloalkyl), —CHO, —COOH, and hydrocarbyl having a hydrocarbon chain of 1 to 3 carbon atoms in which the carbon atoms are joined by single, double or triple bonds, and any one carbon atom or any two nonadjacent carbon atoms can be replaced by O, NH, N(C 1 -C 4  alkyl), or S, and wherein the hydrocarbyl group is optionally substituted with one or more substituents independently chosen from hydroxyl, oxo, halogen, and amino;   B is CR 11 R 12  or NR;   R 11  and R 12  are each independently hydrogen, halogen, hydroxyl, cyano, nitro, amino, —CHO, —CONH 2 , C 1-3  alkyl (such as methyl), C 1-3  alkoxy, C 1-2 haloalkyl, and C 1-2 haloalkoxy;   R 7 , R 8 , R 9 , and R 10  are each independently hydrogen, halogen, hydroxyl, cyano, nitro, amino, —CHO, —CONH 2 , —NR 13 —CO—R 14 , —CO-aryl (such as —CO—C 6  or C 8  aryl or benzoyl), —CO— alkyl (such as —CO—C 1-6  alkyl or acetyl), alkyl (such as C 1-6  alkyl or methyl), alkoxy (such as C 1-4  alkoxy), cycloalkyl (such as C 3-8  cycloalkyl), haloalkyl (such as C 1-2 haloalkyl), haloalkoxy (such as C 1-2 haloalkoxy), aryl (such as a C 6  or C 8  aryl), heteroaryl (such as 5-8, 5, or 6 membered heteroaryl, furyl, thienyl, or pyrrolyl), heterocycloalkyl (such as a 3-8 membered heterocycloalkyl), an aryloxy (such as phenoxy), alkylaryl (such as —CH 2 —CH 2 -phenyl), or a thioaryl (such as thiophenyl);   R 13  and R 14  are each independently hydrogen, alkyl (such as C 1 -C 6  alkyl), alkoxy (such as C 1 -C 4  alkoxy), cycloalkyl (such as C 3 -C 8  cycloalkyl), haloalkyl (such as C 1 -C 2 haloalkyl), aryl (such as phenyl, naphthyl, or tolyl), heteroaryl (such as furyl, thienyl, or pyrrolyl), and heterocycloalkyl (such as 5-8, 5, or 6 membered heterocycloalkyl);   a combination thereof.   
     
     
         13 . The method of  claim 12 , wherein
 A 3  is a C 6  aryl or 6-membered heteroaryl;   A 3  is optionally substituted with 1 or 2 substituents independently selected from halogen (such as Br, F, I, or Cl), —NR 11a —CO—R 12a  (such as —NH—CO—R 12a ), hydroxyl, cyano, nitro, amino (such as —NH 2 ), C 1-3  alkyl (such as methyl), C 1-4  alkoxy (such as methoxy), C 3-8  cycloalkyl, C 1-2  haloalkyl, C 1-2 haloalkoxy, C 6  aryl, C 8  aryl, 5-8 membered heteroaryl, 3-8 membered heterocycloalkyl (such as 5-8 membered heterocycloalkyl), —CHO, and —COOH;   R 11a  is a hydrogen or a C 1-3  alkyl;   R 12a  is a 5-8 membered heteroaryl (such as 5, 6, or 7 membered heteroaryl), 9-11 membered bicyclic heteroaryl (such as 10 membered bicyclic heteroaryl), C 6  monocyclic aryl, C 8  monocyclic aryl, or C 9-11  bicyclic aryl (such as C 10  bicyclic aryl), wherein the R 14a  is optionally substituted with 1, 2, or 3 substituents independently selected from halogen (such as Cl, Br, I, or F), or C 1-3  alkyl (such as methyl), and C 1-3  alkoxy (such as methoxy);   R 7 , R 9 , and R 10  are each hydrogen;   A is N;   B is NR 11 ;   R 11  is hydrogen or C 1-6  alkyl (such as C 1-3  alkyl or methyl);   R 13  is a hydrogen or a C 1-3  alkyl;   R 14  is hydrogen, alkyl (such as C 1 -C 6  alkyl), alkoxy (such as C 1 -C 4  alkoxy), cycloalkyl (such as C 3 -C 8  cycloalkyl), haloalkyl (such as C 1 -C 2 haloalkyl), aryl (such as phenyl, naphthyl, or tolyl), heteroaryl (such as furyl, thienyl, or pyrrolyl), and heterocycloalkyl (such as 5-8, 5, or 6 membered heterocycloalkyl); a combination thereof; or   a combination thereof.   
     
     
         14 . The method of  claim 13 , wherein A 3  is a C 6  aryl or 6-membered heteroaryl having the chemical structure 
       
         
           
           
               
               
           
         
       
       wherein:
    is the point of attachment with Formula II; 
 each V is independently a CH or N, wherein there 0, 1, 2, 3, or 4 N groups; and 
 R 15 , R 16 , and R 17  are independently selected from halogen (such as Br, F, I, or Cl), —NR 13a COR 14a  (such as —NHCOR 14a ), hydroxyl, cyano, nitro, amino (such as —NH 2 ), C 1-3  alkyl (such as methyl), C 1-4 alkoxy (such as methoxy), C 3-8  cycloalkyl, C 1-2 haloalkyl, C 1-2 haloalkoxy, C 6  aryl, C 8  aryl, 5-8 membered heteroaryl, 3-8 membered heterocycloalkyl (such as 5-8 membered heterocycloalkyl), —CHO, and —COOH, wherein 
 one of R 15 , R 16 , and R 17  is a hydrogen; and 
 one of R 15 , R 16 , and R 17  is a hydrogen or a C 1-6  alkyl (such as C 1-3  alkyl or methyl). 
 
     
     
         15 . The method of  claim 12 , wherein either (i) or (ii):
 (i) A 3  is an aryl (such as a monocyclic aryl or bicyclic aryl), a heteroaryl (such as a monocyclic heteroaryl or bicyclic heteroaryl), a cycloalkyl (such as a C 3-8  cycloalkyl group), or a heterocycloalkyl (such as a 5-8 membered heterocycloalkyl), wherein:
 (a) one carbon atom (such as R 15 , R 16 , or R 17 ) is —NR 11a —CO—R 12a  (such as —NH—CO—R 12a ), cycloalkyl (such as C 3 -C 8  cycloalkyl), aryl (such as a C 6  or C 8  aryl), heteroaryl (such as a 5-8 membered heteroaryl), heterocycloalkyl (such as a 3-8 or 5-8 membered heterocycloalkyl), —CHO, or —COOH; and 
 (b) a second carbon atom (such as R 15 , R 16 , or R 17 ) is optionally substituted with a halogen (such as Br, F, I, or Cl), hydroxyl, cyano, nitro, amino (such as —NH 2 ), alkyl (such as C 1-6  or C 1-3  alkyl or methyl), alkoxy (such as C 1-4  alkoxy or methoxy), haloalkoxy (such as C 1-2  haloalkoxy); or 
   (ii) R 7 , R 8 , R 9 , and R 10  are each independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, —CHO, —CONH 2 , —CO-alkyl (such as —CO—C 1-6  alkyl or acetyl), alkyl (such as C 1-6  alkyl or methyl), alkoxy (such as C 1-4  alkoxy), cycloalkyl (such as C 3-8  cycloalkyl), haloalkyl (such as C 1-2 haloalkyl), and haloalkoxy (such as C 1-2 haloalkoxy),
 wherein R 8  or R 9  (such as R 8 ) is —NR 13 —CO—R 14 , —CO-aryl (such as —CO—C 6  or C 8  aryl or benzoyl), —CO-heteroaryl (such as 5-8, 5 or 6 membered heteroaryl), aryl (such as a C 6  or C 8  aryl), heteroaryl (such as 5-8, 5, or 6 membered heteroaryl, furyl, thienyl, or pyrrolyl), heterocycloalkyl (such as a 3-8 membered heterocycloalkyl), an aryloxy (such as phenoxy), alkylaryl (such as —CH 2 —CH 2 -phenyl), and a thioaryl (such as thiophenyl). 
   
     
     
         16 . The method of  claim 9 , wherein either (i) or (ii):
 (i) A 3  is an aryl (such as a monocyclic aryl or bicyclic aryl), a heteroaryl (such as a monocyclic heteroaryl or bicyclic heteroaryl), a cycloalkyl (such as a C 3-8  cycloalkyl group), or a heterocycloalkyl (such as a 5-8 membered heterocycloalkyl), wherein:
 (a) one carbon atom is —NR 11a —CO—R 12a  (such as —NH—CO—R 12a ), cycloalkyl (such as C 3 -C 8  cycloalkyl), aryl (such as a C 6  or C 8  aryl), heteroaryl (such as a 5-8 membered heteroaryl), heterocycloalkyl (such as a 3-8 or 5-8 membered heterocycloalkyl), —CHO, or —COOH; and 
 (b) a second carbon atom is optionally substituted with a halogen (such as Br, F, I, or Cl), hydroxyl, cyano, nitro, amino (such as —NH 2 ), alkyl (such as C 1-6  or C 1-3  alkyl or methyl), alkoxy (such as C 1-4  alkoxy or methoxy), haloalkoxy (such as C 1-2 haloalkoxy); or 
   (ii) R 7 , R 8 , R 9 , and R 10  are each independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, —CHO, —CONH 2 , —CO-alkyl (such as —CO—C 1-6  alkyl or acetyl), alkyl (such as C 1-6  alkyl or methyl), alkoxy (such as C 1-4  alkoxy), cycloalkyl (such as C 3-8  cycloalkyl), haloalkyl (such as C 1-2 haloalkyl), and haloalkoxy (such as C 1-2 haloalkoxy),
 wherein R 8  or R 9  (such as R 8 ) is —NR 13 —CO—R 14 , —CO-aryl (such as —CO—C 6  or C 8  aryl or benzoyl), —CO-heteroaryl (such as 5-8, 5 or 6 membered heteroaryl), aryl (such as a C 6  or C 8  aryl), heteroaryl (such as 5-8, 5, or 6 membered heteroaryl, furyl, thienyl, or pyrrolyl), heterocycloalkyl (such as a 3-8 membered heterocycloalkyl), an aryloxy (such as phenoxy), alkylaryl (such as —CH 2 —CH 2 -phenyl), and a thioaryl (such as thiophenyl). 
   
     
     
         17 . The method of  claim 16 , wherein A 3  is a C 6  aryl or 6-membered heteroaryl having the chemical structure 
       
         
           
           
               
               
           
         
       
       wherein:
    is the point of attachment with Formula II; 
 each V is independently a CH or N, wherein there 0, 1, 2, or 3 N groups; and 
 R 15 , R 16 , and R 17  are independently selected from halogen (such as Br, F, I, or Cl), —NR 13a COR 14a  (such as —NHCOR 14a ), hydroxyl, cyano, nitro, amino (such as —NH 2 ), C 1-3  alkyl (such as methyl), C 1-4 alkoxy (such as methoxy), C 3-8  cycloalkyl, C 1-2 haloalkyl, C 1-2 haloalkoxy, C 6  aryl, C 8  aryl, 5-8 membered heteroaryl, and 3-8 membered heterocycloalkyl (such as 5-8 membered heterocycloalkyl), —CHO, and —COOH, wherein
 one of R 15 , R 16 , and R 17  is a hydrogen; and 
 one of R 15 , R 16 , and R 17  is a hydrogen or a C 1-6  alkyl (such as C 1-3  alkyl or methyl). 
 
 
     
     
         18 . The method of  claim 9 , wherein the compound is selected from compounds 51-67. 
     
     
         19 . A method of treating or preventing a disease or disorder, or symptom associated with a picornavirus infection in a subject, the method comprising:
 providing and administering a therapeutically effective amount of a compound selected from 1-[bis(4-fluorophenyl)methoxy]-3-(5,6-difluoro-1H-1,3-benzodiazol-1-yl)propan-2-ol (compound 108), (4,6-diamino-1,3,5-triazin-2-yl)methyl 3-[5-fluoro-2-(4-fluorophenyl)-1H-indol-3-yl]propanoate (compound 111), 4-(2-{1-[(2-chlorophenyl)methyl]-1H-indol-3-yl}ethenyl)-6-(trifluoromethyl)-1,2-dihydropyrimidin-2-one (compound 139), and N-(3-chlorophenyl)-2-[8-(3-fluorophenoxy)-3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyrazin-2-yl]acetamide (compound 167),   or a pharmaceutically acceptable salt thereof, or a composition comprising the same to the subject,
 wherein the method is effective in treating, preventing, or ameliorating the disease or disorder associated with a picornaviruses infection, or at least one symptom of the disease or disorder associated with a picornavirus infection.